From Cancer to Pain Target by Automated Selectivity Inversion of a Clinical Candidate.

Elimination of inadvertent binding is crucial for inhibitor design targeting conserved protein classes like kinases. Compounds in clinical trials provide a rich source for initiating drug design efforts by exploiting such secondary binding events. Considering both aspects, we shifted the selectivity of tozasertib, originally developed against AurA as cancer target, toward the pain target TrkA.

A validated antibody panel for the characterization of tau post-translational modifications.

Background: Tau is a microtubule-binding protein, which is subject to various post-translational modifications (PTMs) including phosphorylation, methylation, acetylation, glycosylation, nitration, sumoylation and truncation. Aberrant PTMs such as hyperphosphorylation result in tau aggregation and the formation of neurofibrillary tangles, which are a hallmark of Alzheimer's disease (AD). In order to study the importance of PTMs on tau function, antibodies raised against specific modification sites are widely used.

Mutation of Tyr137 of the universal fimbrial adhesin FimH relaxes the tyrosine gate prior to mannose binding.

The most prevalent diseases manifested by are acute and recurrent bladder infections and chronic inflammatory bowel diseases such as Crohn's disease. clinical isolates express the FimH adhesin, which consists of a mannose-specific lectin domain connected a pilin domain to the tip of type 1 pili. Although the isolated FimH lectin domain has affinities in the nanomolar range for all high-mannosidic glycans, differentiation between these glycans is based on their capacity to form predominantly hydrophobic interactions within the tyrosine gate at the entrance to the binding pocket.

KinMap: a web-based tool for interactive navigation through human kinome data.

Background: Annotations of the phylogenetic tree of the human kinome is an intuitive way to visualize compound profiling data, structural features of kinases or functional relationships within this important class of proteins. The increasing volume and complexity of kinase-related data underlines the need for a tool that enables complex queries pertaining to kinase disease involvement and potential therapeutic uses of kinase inhibitors.

Results: Here, we present KinMap, a user-friendly online tool that facilitates the interactive navigation through kinase knowledge by linking biochemical, structural, and disease association data to the human kinome tree.

Profiling Prediction of Kinase Inhibitors: Toward the Virtual Assay.

Kinome-wide screening would have the advantage of providing structure-activity relationships against hundreds of targets simultaneously. Here, we report the generation of ligand-based activity prediction models for over 280 kinases by employing Machine Learning methods on an extensive data set of proprietary bioactivity data combined with open data. High quality (AUC > 0.

Identification and Visualization of Kinase-Specific Subpockets.

The identification and design of selective compounds is important for the reduction of unwanted side effects as well as for the development of tool compounds for target validation studies. This is, in particular, true for therapeutically important protein families that possess conserved folds and have numerous members such as kinases. To support the design of selective kinase inhibitors, we developed a novel approach that allows identification of specificity determining subpockets between closely related kinases solely based on their three-dimensional structures.

Design, synthesis, antimicrobial evaluation and molecular docking studies of some new 2,3-dihydrothiazoles and 4-thiazolidinones containing sulfisoxazole.

Microbial resistance to the available drugs poses a serious threat in modern medicine. We report the design, synthesis and in vitro antimicrobial evaluation of new functionalized 2,3-dihydrothiazoles and 4-thiazolidinones tagged with sulfisoxazole moiety. Compound 8d was most active against Bacillis subtilis (MIC, 0.

Pocketome of human kinases: prioritizing the ATP binding sites of (yet) untapped protein kinases for drug discovery.

Protein kinases are involved in a variety of diseases including cancer, inflammation, and autoimmune disorders. Although the development of new kinase inhibitors is a major focus in pharmaceutical research, a large number of kinases remained so far unexplored in drug discovery projects. The selection and assessment of targets is an essential but challenging area.

Exploring the free-energy landscape of carbohydrate-protein complexes: development and validation of scoring functions considering the binding-site topology.

Carbohydrates play a key role in a variety of physiological and pathological processes and, hence, represent a rich source for the development of novel therapeutic agents. Being able to predict binding mode and binding affinity is an essential, yet lacking, aspect of the structure-based design of carbohydrate-based ligands. We assembled a diverse data set comprising 273 carbohydrate-protein crystal structures with known binding affinity and evaluated the prediction accuracy of a large collection of well-established scoring and free-energy functions, as well as combinations thereof.

Design, synthesis, antimicrobial evaluation and molecular docking studies of some new thiophene, pyrazole and pyridone derivatives bearing sulfisoxazole moiety.

Development of new antimicrobial agents is a good solution to overcome drug-resistance problems. In this context, new functionalized thiophene, acrylamide, arylhydrazone, pyrazole and pyridone derivatives bearing sulfisoxazole moiety were designed, synthesized and evaluated for their in vitro antibacterial and antifungal activities. Among the synthesized compounds, thiophene 4d and 6-thioglucosylpyridone 17 displayed significant antibacterial activities against Escherichia coli (MIC, 0.

Molecular design and synthesis of HCV inhibitors based on thiazolone scaffold.

A series of thiazolone derivatives was designed and synthesized as potential HCV NS5B allosteric polymerase inhibitors at the allosteric site thumb II. Their antiviral activity was evaluated and molecular modeling was utilized to give further envision on their probable binding modes in the allosteric binding site. Among the tested molecules, compound 9b displayed sub-micromolar inhibitory activity with an EC50 of 0.

Analogs design, synthesis and biological evaluation of peptidomimetics with potential anti-HCV activity.

Two series of peptidomimetics were designed, prepared and evaluated for their anti-HCV activity. One series possesses a C-terminal carboxylate functionality. In the other series, the electrophilic vinyl sulfonate moiety was introduced as a novel class of HCV NS3/4A protease inhibitors.

A molecular-modeling toolbox aimed at bridging the gap between medicinal chemistry and computational sciences.

In the current era of high-throughput drug discovery and development, molecular modeling has become an indispensable tool for identifying, optimizing and prioritizing small-molecule drug candidates. The required background in computational chemistry and the knowledge of how to handle the complex underlying protocols, however, might keep medicinal chemists from routinely using in silico technologies. Our objective is to encourage those researchers to exploit existing modeling technologies more frequently through easy-to-use graphical user interfaces.